1. The Field of the Invention
The present invention is related to compositions which are capable of removal of certain metals from the body of animals or humans, and which compositions are capable of oral administration. More particularly, the present invention is related to partially lipophilic polyaminocarboxylic acids and methods for their use in the removal of specific metals from specific organs in the body of a recipient.
2. Technical Background
Metal poisoning is a serious health problem. Metal poisoning can occur in several different contexts and can potentially involve a wide variety of metals. One of the most common types of metal poisoning is lead poisoning. Until recently, lead was commonly included in paints and as a gasoline additive. Accordingly, contact with lead in the urban environment or in the home was very common, and is still a major health concern. Other types of metals are also commonly encountered in the modern environment. For example, workers in metal related industries are constantly placed in environments which may contain unhealthful levels of metals. The same is true of workers in industries which deal with radioactive materials, including nuclear power, scientific research, and mining of radioactive metals.
To appreciate the potential scope of metal poisoning, it is useful to consider lead as an example. Children exposed to lead are known to suffer a number of health problems. These problems range from stomach aches and general irritability, to severe and irreversible brain damage. Children who are exposed to excessive levels of lead are commonly known to suffer from learning disabilities and a reduction in IQ.
In the United States, the primary source of lead poisoning is paint in the home. It is estimated that the walls of 57 million houses in the United States contain lead paint. As a result, the incidence of increased levels of lead in children is widespread. The Environmental Protection Agency estimates that one in nine children under the age of 6 has enough lead in his blood to be considered at risk. The United States Public Health Service places that figure as high as one child in six, and one in two in inner city neighborhoods. As a result, it is apparent that lead poisoning is a very serious health problem in the United States and the effects of the problem can be devastating, not only to the individual but to society as a whole.
Another class of metals that is of concern, and which is dealt with by the present invention, are lanthanide (4f) and actinide (5f) elements. The primary problem presented by contamination by these materials is radiation toxicity, as opposed to chemical toxicity. The increasing use of radioactive materials has introduced greater risk of poisoning by these and other radioactive metals. Indeed, a number of accidents of varying scope have occurred involving these materials. Some of the most notable accidents involving these materials have occurred in Eastern Europe and the Soviet Union. However, smaller incidences of exposure are more common and widespread.
The effects of contamination by actinides and lanthanides is well documented in the literature. In animal studies, malignant neoplasms are known to occur over a wide range of doses. The carcinogenic potential of these elements in humans is not fully known, but cancers would be expected based upon human exposures to other alpha-emitting bone-seeking isotopes, such as radium. Thus, it will be appreciated that the contamination by radioactive elements (nuclides) is also a serious concern.
The most common treatment for metal poisoning is "chelation therapy." Conventional chelation therapy involves intravenous injection of a chelating agent into the patient. Widely known and conventional chelating agents such as EDTA (ethylenediaminetetraacetic acid) and DTPA (diethylenetriamine pentaacetic acid) are often employed. Conventional chelation therapy is very painful to the patient and has only limited effectiveness.
The most commonly used agent for the removal of 5f elements and several other heavy metals from the body is DTPA. DTPA is usually applied either as the calcium or zinc chelate. The soluble sodium salt and the chelates formed are strongly hydrophilic. Therefore, as mentioned above, the preferred route of administration is by intravenous injection, although other forms of administration, such as inhalation, have been proposed or used in animal studies.
More recently, a new group of chelating agents, based on some naturally occurring, bacterially produced iron chelators have been developed and tested. These compounds structurally are linear catechoylamides that preferentially bind the tetravalent plutonium. Most, but not all, of these compounds are also strongly hydrophilic.
In general, strongly hydrophilic properties result in relatively rapid, primarily urinary, excretion. Thus, entry of the drug into cells, the site of the major fraction of metal deposition within the patient, is seriously limited. This property limits the overall effectiveness of the drug. Hydrophilic compounds are usually poorly absorbed from the intestine. Therefore, hydrophilic chelators require parenteral application which, in general, necessitates the presence of a physician or other certified health professional for their administration.
Parenteral application repeated over extended periods is inconvenient to the patient and sometimes difficult to maintain. The effectiveness of the treatment also diminishes rapidly with time after exposure, and the necessity of parenteral administration often increases the critical time period between exposure and first treatment. Very often, long treatment periods are required to achieve the desired reduction of the heavy metal burden.
In summary, metal poisoning and contamination is a serious health problem. Metal poisoning ranges from relatively widespread lead poisoning, to more infrequent cases of poisoning by radioactive actinides and lanthanides. In many situations, however the effect of metal poisoning can range from serious to catastrophic. The effect on the individual and the society as a whole is serious and of major concern.
As mentioned above, the most widely accepted treatment for metal poisoning or contamination is intravenous administration of a chelating agent. Most chelating agents used in this type of therapy, however, are generally hydrophilic, rapidly excreted, and have only limited ability to penetrate cells in order to remove the subject metals. Thus, the use of EDTA in the treatment of lead poisoning, for example, is effective in removing lead in the blood, but is not effective in removing lead which has penetrated the cells.
Furthermore, it is not possible to target specific organs with conventional chelation therapy. Certain metals are more significantly deposited in certain organs than in other organs. Some metals, for example, are significantly deposited in the bone. Thus, in order to provide an effective treatment it is necessary to have a substance which can penetrate the cellular barrier lining the bone surface. This capability is not readily available with conventional chelating agents.
As mentioned above, chelation therapy has other serious limitations. Injections are painful and difficult, particularly when it is necessary to treat children. Repeated treatments are often required. Because of the fact that only metal found in the blood is effectively removed, timing of the treatments is critical.
Accordingly, it would be a significant advancement in the art to provide methods and compositions for treating metal poisoning and contamination which overcame many of the limitations of the conventional art. Specifically, it would be a significant advancement in the art to provide compositions for treating metal poisoning which could be administered orally. It would be an advancement in the art to provide a chemical composition for the treatment of metal poisoning which was sufficiently lipophilic to facilitate passage of the composition across the intestine and across tissue and cellular barriers.
It would be a further significant advancement in the art to provide compositions for the treatment of metal poisoning which could be directed to remove specific metals. It would be another advancement in the art to provide compositions which could target specific organs or sets of organs. It would be a related advancement in the art to provide synthesis parameters for synthesis of compositions which could accomplish targeting of specific metals in specific organs.
Such methods and apparatus are disclosed and claimed herein.